Submissions for variant NM_000124.4(ERCC6):c.1939G>A (p.Glu647Lys)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV002508691	SCV002817960	likely pathogenic	not provided	2024-11-27	criteria provided, single submitter	clinical testing	Identified with a pathogenic ERCC6 variant in a patient with growth failure, cachexia, microcephaly, cataracts, deafness, and clinical photosensitivity in the published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (PMID: 29572252); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29572252)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002508691	SCV003460788	uncertain significance	not provided	2022-02-22	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 647 of the ERCC6 protein (p.Glu647Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ERCC6-related conditions (PMID: 29572252). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002571566	SCV003627523	uncertain significance	Inborn genetic diseases	2022-07-28	criteria provided, single submitter	clinical testing	The c.1939G>A (p.E647K) alteration is located in exon 9 (coding exon 8) of the ERCC6 gene. This alteration results from a G to A substitution at nucleotide position 1939, causing the glutamic acid (E) at amino acid position 647 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700771	SCV005205209	uncertain significance	not specified	2024-06-14	criteria provided, single submitter	clinical testing	Variant summary: ERCC6 c.1939G>A (p.Glu647Lys) results in a conservative amino acid change located in the SNF2, N-terminal domain (IPR000330) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251238 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1939G>A has been reported in the literature in an individual affected with Cockayne Syndrome but the genotype is not clearly shown (Calmels_2018). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 1810135). Based on the evidence outlined above, the variant was classified as uncertain significance.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796737	SCV005415890	likely pathogenic	Cockayne syndrome type 2		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3_Strong+PP4